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核质环境调节p53的时空相分离。

Nucleo-cytoplasmic environment modulates spatiotemporal p53 phase separation.

作者信息

Datta Debalina, Navalkar Ambuja, Sakunthala Arunima, Paul Ajoy, Patel Komal, Masurkar Shalaka, Gadhe Laxmikant, Manna Shouvik, Bhattacharyya Arpita, Sengupta Shinjinee, Poudyal Manisha, Devi Jyoti, Sawner Ajay Singh, Kadu Pradeep, Shaw Ranjit, Pandey Satyaprakash, Mukherjee Semanti, Gahlot Nitisha, Sengupta Kundan, Maji Samir K

机构信息

Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai 400076, India.

Sunita Sanghi Centre of Aging and Neurodegenerative Diseases, IIT Bombay, Powai, Mumbai 400076, India.

出版信息

Sci Adv. 2024 Dec 13;10(50):eads0427. doi: 10.1126/sciadv.ads0427. Epub 2024 Dec 11.

Abstract

Liquid-liquid phase separation of various transcription factors into biomolecular condensates plays an essential role in gene regulation. Here, using cellular models and in vitro studies, we show the spatiotemporal formation and material properties of p53 condensates that might dictate its function. In particular, p53 forms liquid-like condensates in the nucleus of cells, which can bind to DNA and perform transcriptional activity. However, cancer-associated mutations promote misfolding and partially rigidify the p53 condensates with impaired DNA binding ability. Irrespective of wild-type and mutant forms, the partitioning of p53 into cytoplasm leads to the condensate formation, which subsequently undergoes rapid solidification. In vitro studies show that abundant nuclear components such as RNA and nonspecific DNA promote multicomponent phase separation of the p53 core domain and maintain their liquid-like property, whereas specific DNA promotes its dissolution into tetrameric functional p53. This work provides mechanistic insights into how the life cycle and DNA binding properties of p53 might be regulated by phase separation.

摘要

各种转录因子的液-液相分离形成生物分子凝聚物在基因调控中起着至关重要的作用。在此,我们利用细胞模型和体外研究,展示了p53凝聚物的时空形成及其可能决定其功能的物质特性。具体而言,p53在细胞核中形成液态凝聚物,该凝聚物可与DNA结合并进行转录活性。然而,癌症相关突变会促进p53凝聚物的错误折叠并使其部分僵化,同时削弱其DNA结合能力。无论野生型还是突变型,p53进入细胞质都会导致凝聚物形成,随后凝聚物会迅速固化。体外研究表明,诸如RNA和非特异性DNA等丰富的核成分会促进p53核心结构域的多组分相分离并维持其液态特性,而特异性DNA则会促使其溶解为四聚体功能性p53。这项工作为p53的生命周期和DNA结合特性如何通过相分离进行调控提供了机制性见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fec7/11633762/7e4734b650f4/sciadv.ads0427-f1.jpg

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